Cocaine dependence has serious consequences and has proven difficult to treat. We will conduct three rigorous, innovative, controlled medication trials in identified subpopulations. Medication and dose will be major independent variables. Fluoxetine (0 or 40 mg) will be examined in 78 patients diagnosed as depressed (DSM-IV) and cocaine dependent. 40 mg of fluoxetine, has been found to be well tolerated in our previous studies, though not effective for cocaine dependence per se. Disulfiram (0 or 375 mg) will be examined in 80 cocaine dependent patients who abuse alcohol. Some data suggest utility of disulfiram but research is needed with special precautions due to known interaction between 'stimulants' and disulfiram. Agonist (replacement) models have been the most successful medication approaches for drug dependence (e.g. methadone; nicotine). We examined methylphenidate and will now examine sustained release d-amphetamine for cocaine dependence- only subjects in a double blind trial using human laboratory tests as part of the diagnostic work-up for the trial. Medications will be studied on a manual driven behavioral therapy baseline with (i) telephone screening, (ii) medical/behavioral/psychiatric intake; (iii) 2 weeks stabilization and dose run-up; (iv) 12 week medication trial with special safety provisions for study 3 at week 8;(v) 2 week termination period; (vi) 3 month follow-up. Dependent measures include: twice weekly urine screens, retention, attendance at required treatment elements, and self-report measures obtained weekly, monthly, and at follow-up. Assignment will be random. Patients will be stratified based on intake drug screen results. The fluoxetine trial and d-amphetamine trials, but not the disulfiram trial, will be double blind (per reviews). These studies are direct extensions of our work. Our ability to conduct innovative trials with expert data analytic approaches is a major strength of the Center. These studies are conceptually and technically strong, with due regard for safety issues and will yield important data to NIDA and the field regarding therapy-medication combinations in target populations.